Injury to neurons is one health risk associated with amphetamine self- administration. In rats, four injections of methamphetamine during the course of a single day produce long-lasting damage to the dopamine terminals that innervate the striatum, the serotonin-containing processes of the forebrain, and a group of pyramidal and stellate cells located in the somatosensory cortex. Injury to the somatosensory cells is a topic of interest, since the mechanisms underlying that cell injury are largely unknown, and since somesthetic paresthesias are a hallmark of stimulant drug self-administration. In addition, this cortical injury is of interest because it provides evidence for an abnormal, sustained activation of corticostriatal glutamate transmission during methamphetamine administration. A hypothesis is presented to explain how somatosensory neurons die, and to relate their death to the striatal dopaminergic terminal injury. Key to this hypothesis is that somatosensory cortical neurons die as a consequence of prolonged exposure to excitatory somatosensory afference arising as a consequence of the rats' drug-induced movements and their hyperthermia. A significant advance in the ability to study the cortical cell degeneration is the use of a fluorescent dye, Fluoro-Jade, that specifically marks degenerating cells. Several specific aims are proposed, including: (i) characterization of the cortical cell types that die, on the basis of their axonal projections or transmitter phenotype, (ii) the role of vibrissae afference in the cortical cell death, (iii) the role of cortical glutamate receptors and monoamine (norepinephrine, serotonin) receptors in the cortical cell death, and (iv) whether the dying cells undergo DNA fragmentation. All studies will examine the relationship between the cortical cell injury and the damage to striatal dopaminergic processes, thereby providing a test for the hypothesis that the cortical cell excitation/degeneration is necessary for the striatal dopamine terminal injury.